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Second-line sorafenib plus carboplatin/paclitaxel did not improve PFS in melanoma

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Final results of a phase-3, randomized study demonstrated that sorafenib combined with carboplatin and paclitaxel as second-line treatment for unresectable stage III/IV melanoma was not superior to carboplatin/paclitaxel alone. Response rates differed by only 1% between the control and treatment arms.

The study, which was first presented at the 2007 ASCO Annual Meeting, included 270 patients with advanced melanoma. Patients were randomly assigned to IV paclitaxel 225 mg/m² plus IV carboplatin at an area under curve six on day one of a 21-day cycle. One hundred thirty-five patients then received placebo and 135 received oral sorafenib (Nexavar, Bayer) 400 mg twice daily on days two to 19.

The primary endpoint was PFS; OS and best response were secondary and tertiary endpoints.

PFS did not differ significantly between the two arms: 17.9 weeks for carboplatin and paclitaxel alone vs. 17.4 weeks for sorafenib plus carboplatin and paclitaxel. At the final survival assessment in May 2007, 66% of patients in the placebo arm and 67% of those in the sorafenib arm had died. Median OS for both groups was 42.0 weeks (HR=1.01; 95% CI, 0.76-1.36).

By September 2006, confirmed partial response occurred in 11% of patients in the placebo arm and 12% of patients in the sorafenib arm; there were no confirmed complete responses.

“One important question that remains unanswered is whether the addition of sorafenib to carboplatin and paclitaxel will improve efficacy with respect to CP alone in the first-line setting,” the researchers wrote. A phase-3 trial (E2603) is currently investigating the use of sorafenib plus carboplatin and paclitaxel as first-line treatment in chemotherapy-naive patients with advanced disease, according to the researchers. – by Stacey L. Adams

Hauschild A. J Clin Oncol. 2009;doi:10.1200/JCO.2007.15.7636.

This multicenter phase-3 study was designed to test two hypotheses: combination chemotherapy of carboplatin and paclitaxel (CP) as an effective second-line therapy in advanced melanoma, and combining CP with a tyrosine kinase inhibitor, sorafenib, that should improve the clinical efficacy. In this report, the investigators showed both regimens have acceptable toxicity profiles, but the addition of sorafenib does not improve the clinical efficacy. The response rates were similar and low, 11% for CP alone and 12% for CP plus sorafenib; median overall survival was 42 weeks for both.

These results are very disappointing since sorafenib was originally designed as a targeted therapy for BRAF mutation, and very promising results were shown in melanoma preclinical studies. Most recently, sorafenib has been approved by the FDA for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma based on its activity as a multikinase inhibitor targeting VEGF and PDGF receptors. Currently, several new small molecules, which target BRAF mutation have been developed and are already in phase-1/2 clinical trials. Preliminary results are very promising as a single-agent therapy in metastatic melanoma patients with BRAF mutation.

– Wen-Jen Hwu, MD, PhD

HemOnc Today Editorial Board member